1. Field of the Invention
This invention relates to novel chemicals which are useful as antibacterial agents and, more specifically, to aminoglycosides such as 3',4'-dideoxykanamycin A and derivatives thereof prepared by a selectively acylating the 1-amino function with a .alpha.-hydroxy-.omega.-aminoalkanoyl moiety.
2. Description of the Prior Art
Kanamycins A and B were first described by Hamao Umezawa et al. as in U.S. Pat. No. 2,931,798.
3',4'-Dideoxykanamycin B was disclosed by Hamao Umezawa et al. in U.S. Pat. No. Re. 28,647 (from U.S. Pat. No. 3,753,973) and additional processes for its preparation were given by H. Umezawa et al. in U.S. Pat. No. 4,156,078 and 4,169,939 and in pending U.S. application Ser. No. 745,016 filed Nov. 26, 1976 (and abstracted as Farmdoc 41695Y).
Hamao Umezawa et al. disclosed 3',4'-dideoxykanamycin C in U.S. Pat. No. 4,120,955.
1-N-[.alpha.-Hydroxy-.omega.-aminoalkanoyl] derivatives of 3',4'-dideoxykanamycin B etc. were disclosed in U.S. Pat. No. 4,001,208 and corresponding derivatives of kanamycin A and B were disclosed in U.S. Pat. Nos. 3,781,268, 3,886,139 and 3,904,597 with improved processes set forth in U.S. Pat. Nos. 472,781 and 472,780.
6'-N-Methyl-1-N-[.alpha.-hydroxy-.omega.-aminoalkanoyl] derivatives of 3',4'-dideoxykanamycin B were described by H. Umezawa et al. in U.S. Pat. No. 4,147,861.
1-N-[.alpha.-Hydroxy-.omega.-aminobutyryl]-6'-methyl derivatives of kanamycins A and B were described by Umezawa et al. in U.S. Pat. No. 4,170,642 and 4,001,208 respectively (and see also Farmdoc abstract 46482X).
Some of the present inventors, H. Umezawa et al have found that drug-resistant strains of gram-negative bacteria isolated from patients, resistant Staphylococcus aureus and Pseudomonas aeruginosa and some kinds of resistant bacteria produce an enzyme (phosphotransferase) which is capable of phosphorylating 3'-hydroxyl group of kanamycin A, kanamycin B and other analogous aminoglycosidic antibiotics, and that these aminoglycosidic antibiotics can lose their antibacterial activity by phosphorylation of the 3'-hydroxyl group through the action of the phosphorylating enzyme ("Science" Vol. 157, pages 1559-1561 (1967)). After this finding was obtained, extensive researches have been made about the mechanism of resistance of bacteria to aminoglycosidic antibiotics. At present, it is found that one or some of hydroxyl groups present in the aminoglycosidic antibiotic, such as hydroxyl groups at the 4'- and/or 2"-positions of the aminoglycoside molecule can be phosphorylated or adenylylated by a wide variety of resistant bacterial strains so that the parent aminoglycosidic antibiotic can lose the antibacterial activity. Based on this finding, we already semi-synthetically prepared many semi-synthetic aminoglycosidic antibiotic derivatives which are active even against the resistant strains. Among the semi-synthetic aminoglycosidic antibiotic derivatives, 3',4'-dideoxykanamycin B (see U.S. Pat. No. 3,753,973) is known under the general name "dibekacin" and is now used widely in therapeutic treatment of bacterial infections in clinics, because dibekacin is remarkably active against a wide variety of resistant bacteria.
It was very epochal to make the discovery that the removal of 3'- and 4'-hydroxyl groups from kanamycin B, that is, the 3',4'-di-deoxygenation of kanamycin B gives a semi-synthetic substance which does not lose the antibacterial activity of the parent material kanamycin B but rather attain an improved or modified antibacterial activity even against the resistant bacteria.
On the other hand, it was known that butirosins which were aminoglycosidic antibiotics produced by a Bacillus species were active against some kanamycin- and ribostamycin-resistant bacteria. These butirosins have been identified as 1-N-((S)-2-hydroxy-4-aminobutyryl)-5-O-.beta.-D-xylofuranosyl- or ribofuranosyl-neamine [see the "Tetrahedron Letters" Vol. 28, pages 2617-2620 (1971)].
From comparison of the antibacterial activity of ribostamycin with that of butirosin B, it was discovered the (S)-2-hydroxy-4-aminobutyryl substituent on 1-amino group of butirosins has an important role in making ribostamycin highly active even against the resistant bacteria. From this discovery, it was deduced that an aminoglycosidic antibiotic can be imparted with an anti-bacterial activity against the resistant bacteria by introducing an aminoacyl group into the 1-amino group of an aminoglycosidic antibiotic. After this discovery, the 1-N-aminoacylation has been applied to a variety of aminoglycosidic antibiotics. A successful application of the 1-N-aminoacylation is exemplified by amikacin (also termed as BB-K8), that is, 1-N-((S)-2-hydroxy-4-aminobutyryl)-kanamycin A (see the "Journal of Antibiotics" Vol. 25, pages 695-708 (1972); U.S. Pat. No. 3,781,268).
In spite of the presence of 3'- and 4'-hydroxyl groups in the amikacin molecule, amikacin cannot be inactivated by the kanamycin-resistant bacteria owing to that the 3'- and 4'-hydroxyl groups can neither be phosphorylated nor be adenylylated under the action of the 1-N-((S)-2-hydroxy-4-aminobutyryl) substituent of amikacin. While, as amikacin is applied much more frequently and widely in clinics, new types of the resistant bacteria which are resistant to amikacin are going to occur. In the most recent years, there have been made some reports to show that the 4'-hydroxyl group of amikacin is adenylylated by certain new strains of the resistant bacteria, and that the 3'-hydroxyl group of amikacin is phosphorylated (see the "Antimicrobial Agents and Chemotherapy" pages 619-624 (1977), for example).
In view of the above-mentioned facts and observations, we expect that if the 3'-and 4'-hydroxyl groups can be removed from kanamycin A, the 3',4'-dideoxykanamycin A so possibly obtained will be active against the new types of the resistant bacteria, too.
However, it has been confirmed experimentally that when kanamycin A is merely subjected to the method of deoxygenation comprising 3',4'-di-O-sulfonylation and subsequent treatment of the 3',4'-di-O-sulfonic acid ester with sodium iodide and zinc powder which was successfully applicable in the semi-synthesis of 3',4'-dideoxykanamycin B, there cannot yet be obtained 3',4'-dideoxykanamycin A as expected. This is because the kanamycin A molecule contains 2'-hydroxyl group adjacent to the 3'-hydroxyl group thereof so that this 2'-hydroxyl group can be sulfonylated concurrently to the sulfonylation of the 3'- and 4'-hydroxyl groups, with a consequence that the 2'-hydroxyl group once sulfonylated can be removed at the same time as when the removal of the sulfonylated 3'- and 4'-hydroxyl groups is performed by treating with sodium iodide and zinc powder.
Accordingly, we have considered that 3',4'-dideoxykanamycin A cannot be synthetized from kanamycin A by applying thereto the same deoxygenation method as the one which was adopted in the synthesis of 3',4'-dideoxykanamycin b from kanamycin B, unless we are not able to prepare and provide such a protected kanamycin A derivative which is to be subjected to the procedure of de-oxygenation as mentioned above and of which the 3'- and 4'-hydroxyl groups of kanamycin A remain in the unprotected state, while the neighboring 2'-hydroxyl groups as well as all the other hydroxyl groups and all the amino groups are existing in the protected or blocked state. However, no great difference is observed between the 2'-, 3'- and 4'-hydroxyl groups of kanamycin A in respect of their reactivity, and hence it was very difficult to find out any procedure by which the 2'-hydroxyl group can be protected with retaining the 3'- and 4'-hydroxyl groups unblocked.
We have researched extensively in an attempt to provide such suitable kanamycin A derivative. As a result, we have now found that such a protected derivative of kanamycin A having 3'- and 4'-hydroxyl groups unblocked, having a protected or unprotected 2"-hydroxyl group and having the other hydroxyl groups (including 2'-hydroxyl group) as well as all the amino groups blocked is prepared by means of a combination of an ingenious choice of the nature of the hydroxyl-protecting and amino-protecting groups employed, with an elaborate arrangement of the sequence of the respective stages of protecting each amino group and each hydroxyl groups, in such a way that the 6'-amino group of kanamycin A which is the most reactive among the four amino groups of kanamycin A is at first blocked by an alkoxycarbonyl group, an aralkyloxycarbonyl group, especially benzyloxycarbonyl group or an aryloxycarbonyl group known as one of the conventional amino-protecting groups; the 1-, 3- and 3"-amino groups of kanamycin A are then protected with a hydrocarbylsulfonyl group such as an alkylsulfonyl group, an arylsulfonyl group or aralkylsulfonyl group; the free 4'-hydroxyl group and the alkoxycarbonylated, aralkyloxycarbonylated or aryloxycarbonylated 6'-amino group are subsequently condensed with each other into the form of a cyclic carbamate by treating with e.g. sodium hydride, resulting in a simultaneous protection of the 4'-hydroxyl and 6' -amino groups; a pair of the 5-hydroxyl group and 2'-hydroxyl group are selectively and simultaneously blocked by introducing and bridging therebetween with a known divalent hydroxyl-protecting group such as an alkylidene group, specially isopropylidene group, cyclohexylidene group, benzylidene group or tetrahydro-4-pyranylidene group; the 4',6'-carbamate ring once formed is ring-fissioned by treatment with an alkali to regenerate the free 4'-hydroxyl group and the free 6'-amino group; and finally the free 6'-amino group is blocked with an alkoxycarbonyl or aralkyloxycarbonyl group or an alkanoyl group such as acetyl. In this way, we have succeeded in preparing a desired, suitable protected derivative of kanamycin A, and as a consequence of it, we have now succeeded to provide a route by which semi-synthesis of 3',4'-dideoxykanamycin A is achieved.
Thus, we have now firstly succeeded in synthetizing the new compound, 3',4'-dideoxykanamycin A, and we have also succeeded in synthetizing a 1-N-(.alpha.-hydroxy-.omega.-aminoalkanoyl)-3',4'-dideoxykanamycin A, particularly 1-N-(2-hydroxy-3-aminopropionyl)-3',4'-dideoxykanamycin A and 1-N-((S)-2-hydroxy-4-aminobutyryl)-3',4'-dideoxykanamycin A by condensing the 1-amino group of 3',4'-dideoxykanamycin A with an isoseryl group, particularly DL- or L- or D-2-hydroxy-3-aminopropionyl group, or with (S)-2-hydroxy-4-aminobutyryl group. We have further found that the new derivative of kanamycin A which we have now synthetized are active against a wide variety of the resistant bacteria.